Abstract In response to the NIH RFA-EB-17-003 on ?Proof of Concept Development of Early Stage Next Generation Human Brain Imaging?, we propose a two-year plan to develop the much needed hardware and software solutions for ultrahigh resolution diffusion MRI to delineate cortical columns and layers in the gray matter throughout the brain, on a 3 Tesla magnetic field strength that is accessible by the majority of neuroimaging researchers. As a result, we will have the new generation of innovative RF/shim and gradient coil technologies, as well as pulse sequences, to reach ultrahigh resolution for diffusion MRI in vivo without confounds from magnetic susceptibilities artifacts and physiological contaminations. The proposed development is significant in that it may lead to much earlier detection of the subtle microstructural changes in neurodegenerative diseases (e.g. Alzheimer?s disease (AD), Parkinson?s disease (PD), etc.) well before the symptoms develop. For example, AD is generally believed to originate from microstructural impairments in cortical neurons. Conventional MRI techniques, while sufficient for delineating the late-stage brain structural atrophy (e.g. in hippocampus for AD), have failed to detect these early but subtle neuronal impairments. Risk factors such as ?-amyloid plaques, Tau proteins, and APOE4+ genes, can be found very early in the brain, but do sufficiently predict AD. A definitive early biomarker would be the initial microstructural neuronal deficits (e.g. dendritic density loss and the subsequent diffusion anisotropy reduction) in specific cortical columns and layers, which can be detected very early by ultrahigh resolution diffusion MRI in vulnerable populations. Based on our progress over the past several years in ultrahigh resolution diffusion MRI, we have developed a reliable and robust strategy to reach the necessary isotropic submillimeter resolution (0.6 mm or higher) to resolve cortical columns and layers, and believed that the ultrahigh diffusion measures could provide earlier and more differentiating biomarkers. At the same time, we have also identified key challenges in MRI hardware and acquisition methodology that currently limit the effectiveness and practical utility of ultrahigh resolution diffusion MRI. We will address these challenges in two specific aims: 1) development of an iPRES AIRcoil array (the next-generation RF/shim coils based on GE?s AIR Technology?) to reach high magnetic field uniformity and high SNR throughout the human brain including deep gray matters implicated early in neurodegenerative diseases, 2) development of ultrahigh resolution diffusion MRI acquisition methodologies that are immune to minute brain motions (e.g. cardiac pulsation) to reach true ultrahigh resolution with high sensitivity and efficiency to resolve gray matter cortical columns and layers. We anticipate that this focused two-year R01 project will provide basic science and clinical researchers a much needed noninvasive imaging tool to investigate the intricate and fine-grained cortical microstructure, and ultimately, lead to very early detection of neurodegenerative disorders.